尿液邻苯二甲酸酯类课件

Associations between phthalates exposure and health outcomes of newborns, pregnant women and precocious puberty girls in Taiwan 李俊璋 教授 國立成功大學工業衛生科暨環境醫學研究所 成功大學環境微量毒物研究中心 2 Whats Phthalates (PAEs)? PAEsPAEs They are a family of chemical substances that have been in use for about 50 years, primarily to make polyvinyl chloride (PVC) soft and flexible. Phthalates look like clear vegetable oil. Phthalic acidPhthalic anhydride -H2O ROH General chemical structure of phthalate ester Physico-chemical properties of Phthalates Compounds Dimethyl phthalate DMP Diethyl phthalate DEP Di-n-butyl phthalate DBP Butyl benzyl phthalate BBzP Di(2- ethylhexyl) phthalate DEHP Chemical formula C10H10O4C12H14O4C16H22O4C19H20O4C24H38O4 Molecular weight194.19222.23278.35312.35390.62 Melting point (C)5.5- 40.5- 35- 35- 47 Boiling point (C)282295302340370386 Vapor pressure (mmHg) 1 (100C)1.6510-32.710-5610-7110-7 Soubility (mg L-1, ) 40001000130.70.3 Log Kow 4.97.5 Log Koc1.9-2.61.8-2.73.1-4.23.2-4.24.9-6.0 MetabolitesMMPMEPMBPMBzP MEHP, MEOHP, MEHHP Applications of phthalates Childrens toysPersonal care productsMedical devices Food packaging Building materials Application of phthalates Metabolic pathway of DEHP -Albro, et al., 1982; ATSDR, 1993, Schmid, et al., 1985c. DEHPMEHPHuman Primary Secondary Objectives Part I: Association between Phthalate Exposure and Thyroid Hormone in Pregnant Women Human Reproduction 22, 2715-2722 (2007) To determine the concentrations of urinary phthalate monoesters in pregnant women. To investigate the association between phthalate exposure and thyroid hormone during pregnancy. Objectives Part II: Association between Prenatal Exposure to Phthalates and the Health of Newborns To determine the concentrations of amniotic fluid phthalate monoesters in pregnant women. To evaluate the association between prenatal exposure of the fetus to phthalates in amniotic fluid and maternal urine and the health of newborns. To follow-up our previously established participants in order to determine the correlation between phthalate exposure and thyroid hormones in pregnant women and newborns. Objectives Part III: Phthalates may alter thyroid hormones in utero: A follow-up study Correlation between urinary m-PAEs and thyroid hormone in pregnant women. Correlation between amniotic fluid m-PAEs and the health of newborns. Correlation between cord blood m-PAEs and thyroid hormone in newborns. Correlation of m-PAEs among amniotic fluid, urine, serum and cord blood. Association between Phthalate Exposure and Health Effects of Pregnant Women and Newborns in Taiwan Conc. of urinary m-PAEs Conc. of m-PAEs in serum Serum thyroid hormone (TSH, T4, T3, FT4) Demographic characteristics (Age, gestation, smoke etc.) Pregnant WomenNewborns Conc. of m-PAEs in amniotic fluid Conc. of m-PAEs in cord blood Cord blood thyroid hormone (TSH, T4, T3, FT4) Health status of newborns (Anogenital distance, birth wt., etc.) To choose the susceptible population from the possibly highest phthalate exposure population in Taiwan Provide an insight of potential health effects of phthalate exposure in pregnant women and newborns. Framework q Newborns health qAnogenital distance qGestational age q Urine sample qPhthalate monoesters q Serum the coefficient variations of T3, T4, free T4, and TSH were 2.9%, 4.2%, 3.1%, and 3.0%, respectively. TSHT3T4FT4AgeBMIGestation TSH1 T30.1451 T40.291*0.709*1 FT40.1720.299*0.761*1 Age0.2030.307*0.218*0.0081 BMI0.0440.3090.1370.0100.1061 Gestation0.1060.0180.0380.0570.0290.1311 MBP0.0790.2340.248*0.368*0.0820.081*0.098 MEP0.0820.0190.0390.0170.0800.095*0.199 MEHP-0.0600.0670.1000.0900.1660.0300.030* MBzP0.0800.0840.0340.0070.0640.0270.118 MMP0.0780.2590.0890.0070.0380.0060.004 Table I-4 Spearman correlation coefficients a between thyroid hormone, age, BMI, duration of gestation and urinary phthalate monoester levels (n = 75). a Spearman correlation coefficients, *: p |t|EstimateProb|t| Intercept 1.2700.0132.3620.001 Age 0.0240.886-0.3210.177 BMI 0.0880.5790.3480.120 Gestational age -0.1170.598-0.0660.831 MBP -0.110 Table II-2 Concentrations of five phthalate monoesters in amniotic fluid from female and male infants (ng/mL, n=64)1. Female infantsMin10th50th90thMax MBP39.345.685.5134.6192.0 MEHPND25.024.091.1148.0 MEPNDNDND3.96.5 MBzPNDNDND84.1233.0 MMPNDNDNDND2.92 Male infantsMin10th50th90thMax MBP28.444.381.3127.8145.0 MEHPND22.622.1100.6110.0 MEPNDNDND4.47.7 MBzPNDNDND87.9104.0 MMPNDNDNDNDND 1One amniotic fluid sample was failed during analysis. 2ND=not detected, detection limit of MMP, MEP, MBP, MBzP and MEHP were as follow: 1.4, 1.0, 1.4, 1.4, 0.9 ng/mL Figure II-1 Distribution plot of MBP levels in maternal urine and amniotic fluid (n=59). All the data were log-transformed. n It is indicated that current levels of exposure to phthalate in pregnant women may only partly represent in utero fetal exposure Table II-3 Distribution of health status in females categorized by median levels of phthalate monoester in amniotic fluid (-AF) (n = 31). Health status in female infants MBP-AF2MEHP-AF3 Low4 (n=15) High4 (n=16) P-value1 Low4 (n=15) High4 (n=16) P-value1 Birth weight (g)281043931723980.031*291844830614670.527 Birth length (cm)47.32.318*2.40.138 Gestational age (weeks) 38.11.538.71.00.20538.40.991 AGD (mm)17.64.024*17.00.109 AGI-W (mm/kg)1.50.007*6.00.016* AGI-L (103)0.80.008*0.90.015* 1Wilcoxon Rank Sum Test, *: p 0.05; 2AGD data were lacking for one female newborn in each group. 3AGD data were lacking for two female newborns in the high MEHP-AF group. 4Median levels of amniotic fluid MBP in low and high group were 67 and 104 ng/mL, respectively; those of MEHP were 9.5 and 38.8 ng/mL, respectively. Table II-4. Distribution of health status in boys category by median levels of phthalate monoester in amniotic fluid. (n = 33). Health status in male infants MBPMEHP Low (n=16) High (n=17) P-value Low (n=16) High (n=17) P-value Birth weight (g)314648131944690.640321344031315150.815 Birth length (cm)49.22.550.02.80.70549.42.449.73.00.971 Gestational age (weeks) 39.11.09639.10.987 AGD (mm)21.26.53423.36.806 AGI-W (mm/kg)2.20.201.70.635 AGI-L (103)1.20.301.00.649 1 One male infant of each group in MBP-AF and MEHP-AF, respectively, were lack of AGD. MMPMEPMBPMBzPMEHPBWBLGA BW0.150.070.160.360.171 BL0.29#0.010.200.350.100.83*1 GA0.220.060.43*0.48*1 AGD0.420.100.31#0.020.46* AGI-W0.410.100.32*0.320.030.58*0.54*0.54* AGI-L0.440.100.33*70.27#0.50* Table II-5 Spearman correlation coefficients1 between birth weight, birth length, gestational age, AGD, AGI-W, AGI-L, and phthalate monoester levels in amniotic fluid in female infants (n = 29)2. 1 *:p 0.05; #: p0.06. 2 BW=birth weight, BL=birth length, GA=gestational age, AGD=ano-genital distance, AGI-W=AGD/BW, AGI-L=AGD/ BL Figure II-2 (A) Linear regressions between MBP in amniotic fluid and AGI-W in females at birth (n=29, R2=0.14, p=0.043); (B) Linear regressions between MBP in amniotic fluid and AGI-L in females at birth (n=29, R2=0.16, p=0.032). AB Negative associations among amniotic fluid MBP and AGINegative associations among amniotic fluid MBP and AGI Figure III-3 Multiple regression of AGI, MBP in amniotic fluid and gestational age adjustment of gestational age and other phthalate monoesters (amniotic fluid MBP: = 2.73, p = 0.041; gestational age: = 0.899, p = 0.006) . Table III-1 Concentrations of phthalate monoesters in urine, serum and cord blood at delivery (ng/mL, n=61). Mono- PAEs UrineSerumCord blood Median (Range) 10-90th Median (Range) 10-90th Median (Range) 10-90th MBPa 114 (25.4-1830) 36.9-550.6 158.0 (59.6-1080) 64.9-413.0 256.0 (65.2-815) 97.4-604.8 MEHP 40.2 (3.6-958) 8.4-152.0 21.0 (9.2-99.2) 11.7-37.1 24.7 (11.0-665.0) 14.2-65.9 MEP 36.4 (NDb-1980) 4.6-236.8 2.8 (ND-26.5) ND-6.3 ND (ND-9.3) ND-3.4 MBzP 5.7 (ND-218.0) 1.9-49.2 ND (ND-10.1) ND-2.8 ND (ND-26.8) ND-3.6 MMP 8.3 (ND-169) 1.7-38.0 ND (ND-3.7) ND-2.4 ND (ND-13.3) ND-ND aMBP = monobutyl phthalate; MBzP = monobenzyl phthalate; MEP = monoethyl phthalate; MEHP = mono-2-ethylhexyl phthalate; MMP = monomethyl phthalate. bDetection limit (LOD) of phthalate monoesters were: MBP, 1.4; MBzP, 1.4; MEP, 1.0; MEHP, 0.9; MMP, 1.4 ng/mL, respectively. Half of LOD was calculated as the detected value below the LOD. Table III-2 Concentrations of thyroid hormones1 in maternal serum during pregnancy and cord blood at delivery (n=61). Serum Thyroid Hormones First-trimesterSecond-trimesterThird-trimesterCord blood MedianRangeMedianRangeMedianRangeMedianRange TSH (IU/mL) 1.130.01-4.381.060.23-5.192.080.38-6.077.051.63-289 T3 (ng/dL)12370.2-23013472.6-24614082.4-27756.335.1-84.6 T4 (g/dL)8.263.37-12.19.014.39-13.49.623.60-16.97.663.65-11.7 FT4 (ng/dL)0.950.62-1.290.930.46-1.290.990.33-1.311.130.49-1.45 1Reference values for thyroid hormones in Taiwan: TSH: 0.27-4.2; T 3: 84.6-202.0; T4: 5.13-14.1; FT4: 0.93-1.7. The analytic sensitivities of T3, T4, free T4, and TSH were 19.5 ng/dL, 0.42 g/dL, 0.023 ng/dL and 0.014 lU/mL, respectively. The coefficient variations of T3, T4, free T4, and TSH were 3.0%, 4.1%, 3.2%, and 2.9%, respectively. Table III-3 Correlation a coefficients between fetal thyroid hormones and phthalate monoesters in cord blood samples (n=60)a . Maternal age Gestationa l age MBP-CbMEHP-CbMEP-CbMBzP-CbMMP-Cb Maternal age 10.208-0.073 0.0070.045-0.135#0.112 Gestational age 0.20810.028 0.0160.1500.2290.063 TSH0.176-0.396-0.277#0.1090.108-0.084-0.043 T4 0.0780.0343-0.157#-0.045-0.0260.038-0.136 T3-0.133-0.0690.0790.2110.183-0.053-0.003 FT4-0.1120.1030.162-0.0620.0490.003-0.109 TSHT40.183-0.389-0.230*0.0960.124-0.101-0.072 TSHFT40.169-0.390-0.214#0.0950.128-0.109-0.069 FT4/T30.0710.084-0.027-0.213-0.1040.006-0.096 FT4/T4-0.2000.0610.346*0.0170.066-0.0490.102 T3/T4-0.072-0.1620.133#0.1470.122-0.0570.091 T4/TSH0.0190.2870.0890.000-0.1310.108-0.002 a Spearman correlation: *p0.01, *p0.05, #p0.1. b-C: Phthalate monoesters in cord blood sample. Figure III-2 Linear correlation between log MBP levels and TSHT4 in cord blood samples (R2=0.081, p=0.028, n=60). Table III-4 Multivariate regression between TSH and T4 and their corresponding phthalate monoesters in cord blood (n=60)a 33 Possible Hypotheses First, we postulated phthalate exposure may affect fetal thyroid function indirectly via decreased thyroid hormones from their mother. Animal studies have shown that in utero exposure to thyroid hormone affects the regulation of the hypothalamus-pituitary-thyroid axis in newborns (Alonso et al., 2007; Piosik et al., 1997). Our previous study showed decreased FT4 and T4 levels with increasing urinary MBP levels in pregnant women during the second trimester (Huang et al., 2007). Second, phthalate monoesters penetrate the human placenta and may have direct effects on fetal thyroid function. Some toxicological studies have shown that certain phthalates, such as DBP and DEHP, are possible thyroxine antagonists that affect the transportation, secretion, and action of thyroid hormones in adult animals (Hinton et al., 1986; Poon et al., 1997; Sugiyama et al., 2005). Although little information is available about phthalate exposure in utero and its effects on fetal thyroid function, some studies (Huang et al., 2007; Meeker et al., 2007) have shown possible negative effects in humans. 性早熟童液中鄰苯二甲酸酯代謝物檢測與 家戶灰塵之相關性研究 The study on relationship between urinary phthalate monoesters and house dust exposure in precocious puberty girls 行政院國家科學委員會補助專題研究計畫成果報告 Phthalate in house dust Table 1. Estimated intakes of phthalates compared with the tolerable daily intake (values in g/kg body weight/day) (Fromme et al., 2007) 36 Exposure route of phthalates INGESTIONSKIN ABSORPTION INHALATION /?cat=572 Children prone to be higher exposed Lower body weight Hand to mouth behavior (sucking/ mouthing dust) Schettler, 2006; Sathyanarayana, 2008; Wittassek, 2010 Fig 1 The framework of this study 38 Sampling strategy for dust- 5 samples Bed (or sofa) Floor Upper floor Major activity area (Sleeping room) Sample 1Sample 2 Sample 5 Minor activity area (Parents room, living room, playroom et al.) Sample 3Sample 4 Kitchen bathroom Parents room Living room Playroom Dust collection equipment Using aluminum-made collector Geometric mean (Range) The analytical results of urine samples Results Table The kisspeptin-54 levels, basal hormones and physical characteristics from part of precocious puberty and normal girls in this study. Trend test: p=0.003 Fig Kisspeptin-54 in different development group. 1: Normal (N=11); 2: LHRH test positive (N=11); 3: Treatment with Leuplin; Menarche (N=15). Fig The association between Kisspeptin-54 and ln MBP-Cr (g/g-Cr). R2= 0.288;p= 0.001 Results Results (Intervention strategies) 介入